The ultimate objective of this study is to understand the mechanism of vertebrate limb formation. The focus of this proposal is on limb development along its proximal-distal axis. Previous studies have established that members of the Fibroblast Growth Factor (FGF) family of secreted signaling molecules play a central role in this developmental context. However, their exact function has remained a disputed issue. Recent genetic data suggest that FGFs are important in establishing the proper size of progenitor populations prior to differentiation. In this study, genetic approaches will be employed to investigate the molecular and cellular basis of FGF function in the control of progenitor population size using mouse as a model organism. In this proposal, the validity of other previously proposed roles of FGFs in limb development would also be addressed. The data generated here will lead to a better understanding of the process of limb proximal-distal development. Since limb formation is a conserved process, our knowledge from the model organisms will provide insights into the basis for human limb defects, and the potential for regeneration of this external organ.